Mechanisms by which LRP1 Protects the Vasculature

LRP1 保护脉管系统的机制

• 批准号: 9002897
• 负责人: Dudley K. Strickland
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002897
• 关键词: Abdominal Aortic Aneurysm; Accounting; Acute; Affect; Amino Acid Substitution; Aneurysm; Aorta; Aortic Aneurysm; Aortic Diseases; Atherosclerosis; Binding; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Cells; Cessation of life; Chest; Chymase; Clinical Data; Collaborations; Collagen; Coronary; Country; DNA; Data; Deposition; Development; Dideoxy Chain Termination DNA Sequencing; Dilatation - action; Disease; Dissection; Elastic Fiber; Elastin; Elderly; Event; Extracellular Matrix; Family; Family member; Filament; Gene Mutation; Genes; Genetic; Genetic Determinism; Genetic study; Health; Heart; High temperature of physical object; Human; Inflammatory; Inherited; Intervention; LDL-Receptor Related Protein 1; Lead; Ligand Binding; Mediating; Modeling; Molecular; Mus; Muscle Contraction; Mutation; Operative Surgical Procedures; Orthologous Gene; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Physiological Processes; Physiology; Plant Roots; Plasma; Process; Proteins; Proteomics; Receptor Signaling; Role; Rupture; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Susceptibility Gene; Symptoms; Testing; Thoracic Aortic Aneurysm; Variant; Vascular Smooth Muscle; age group; exome sequencing; genome wide association study; human disease; in vivo; inhibitor/antagonist; macrophage; mast cell protease 4; prevent; rare variant; receptor; receptor function; research study

DESCRIPTION (provided by applicant): Aortic aneurysms and aortic dissections account for 1% to 2% of all deaths in Western countries, and are usually asymptomatic until they rupture which most often results in death. Unfortunately, our current understanding of the molecular mechanisms leading to aneurysm formation is limited. Genome wide association studies reveal that the Lrp1 gene represents a susceptibility locus for abdominal aortic aneurysms. LRP1 encodes the LDL receptor related protein 1 (LRP1), a large endocytic and signaling receptor that regulates important physiological processes. Our recent studies reveal that mice in which the Lrp1 gene is selectively deleted in smooth muscle cells (smLRP1-/- mice) develop thoracic aneurysms. These mice display all of the symptoms detected in the human disease, including extensive in vivo aortic root and thoracic aortic dilatation, elastic lamina disorganization, recruitment of inflammatory cells into the vessel wall and excess collagen deposition. Proteomic studies revealed accumulation of proteases in the vessel wall, including HtrA1 (high-temperature requirement factor A1) and mast cell protease 4 (mMCP-4), the murine ortholog of human chymase. Both of these proteases are involved in matrix and elastic lamina degradation. Studies in Aim 1 will test the hypothesis that SMC LRP1 protects the vasculature by modulating protease activity, especially HtrA1 and mMCP-4, which in turn regulates the integrity of the elastic laminae. Ultrastructure studies of the aortic wall in smLRP1-/- mice reveal abnormal SMC. The TGF signaling pathway is a major pathway that is responsible for maintaining SMC in a contractile phenotype, and our preliminary data reveal that LRP1 binds several TGF family members and is required for the non-canonical signaling mediated by TGF Experiments in Aim 2 will test the hypothesis that LRP1 modulates SMC phenotypic transitions by regulating the TGF signaling pathway. Finally, we have initiated studies in collaboration with Dianna Milewicz (UT Houston) who has performed exome and Sanger sequencing of DNA from families with thoracic aortic aneurysms and acute aortic dissections. These studies identified several extremely rare LRP1 variants that segregate with aortic disease in these families, providing strong evidence that they are associated with the disease. Analysis of the amino acid substitutions in several of these variants suggest a strong rational for altered ligand binding and altered function in LRP1. Studies in Aim 3 will test the hypothesis that these rare variants result in defective LRP1 function, which in turn contributes to the development of this disease.

描述（由申请人提供）：在西方国家，主动脉瘤和主动脉夹层占所有死亡的1%至2%，通常无症状，直到破裂，最常见的是导致死亡。不幸的是，我们目前对导致动脉瘤形成的分子机制的理解是有限的。全基因组关联研究表明Lrp 1基因是腹主动脉瘤的易感基因。LRP 1编码LDL受体相关蛋白1（LRP 1），一种调节重要生理过程的大型内吞和信号受体。我们最近的研究表明，在平滑肌细胞中选择性删除Lrp 1基因的小鼠（smLRP 1-/-小鼠）发生胸动脉瘤。这些小鼠表现出在人类疾病中检测到的所有症状，包括广泛的体内主动脉根和胸主动脉扩张、弹性膜解体、炎性细胞募集到血管壁中和过量胶原沉积。蛋白质组学研究揭示了蛋白酶在血管壁中的积累，包括HtrA 1（高温需要因子A1）和肥大细胞蛋白酶4（mMCP-4），人类糜酶的小鼠直系同源物。这两种蛋白酶都参与基质和弹性膜降解。目的1中的研究将检验SMC LRP 1通过调节蛋白酶活性（特别是HtrA 1和mMCP-4）保护血管系统的假设，所述蛋白酶活性反过来调节弹性膜的完整性。smLRP 1-/-小鼠主动脉壁的超微结构研究显示异常SMC。TGF信号传导途径是负责维持SMC处于收缩表型的主要途径，并且我们的初步数据揭示LRP 1结合若干TGF家族成员并且是由TGF介导的非经典信号传导所需的。目的2中的实验将检验LRP 1通过调节TGF信号传导途径来调节SMC表型转变的假设。最后，我们与Dianna Milewicz（UT Houston）合作开展了研究，她对胸主动脉瘤和急性主动脉夹层家族的DNA进行了外显子组和桑格测序。这些研究发现了几种极其罕见的LRP 1变异，这些变异与这些家族中的主动脉疾病分离，为它们与疾病相关提供了强有力的证据。对这些变体中的几个中的氨基酸取代的分析表明改变配体结合的强合理性， 改变LRP 1的功能。目标3中的研究将检验这些罕见变异导致 LRP 1功能缺陷，这反过来又有助于这种疾病的发展。